This invention relates to the use of leptin and leptin mimetics to augment bone mass including the prevention and treatment of skeletal disorders such as osteoporosis in vertebrates, e.g., mammals, including humans.
Osteoporosis is a systemic skeletal disorder, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecast to increase three-fold over the next 60 years, and one study estimates that there will be 4.5 million hip fractures worldwide in 2050.
Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
In addition to hip fractures numbering approximately 250,000/year in the U.S., approximately, 20-25 million women and an increasing number of men have detectable vertebral fractures. Hip fracture is associated with a 12% mortality rate within the first two years and with a 30% rate of patients requiring nursing home care after the fracture. While this is already significant, the economic and medical consequences of convalescence due to slow or imperfect healing of these bone fractures is expected to increase, due to the aging of the general population.
There are currently two main types of pharmaceutical therapy for the treatment of osteoporosis and skeletal fractures. The first is the use of anti-resorptive compounds to inhibit the resorption of bone tissue and therefore prevent bone loss and reduce the incidence of skeletal fractures.
Estrogen is an example of an anti-resorptive agent. It is known that estrogen prevents post-menopausal bone loss and reduces skeletal fractures. However, estrogen fails to restore bone to the established osteoporotic skeleton. Furthermore, long-term estrogen therapy, however, has been implicated in a variety of disorders, including an increase in the risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to avoid this treatment. The significant undesirable effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis.
A second type of pharmaceutical therapy for the treatment of osteoporosis and bone fractures is the use of anabolic agents to promote bone formation and increase bone mass. This class of agents is expected to restore bone to the established osteoporotic skeleton by stimulating osteoblastic bone formation. Currently, such pharmaceutical therapy is not available for established osteoporotic patents.
Leptin, a product of the obese gene, is a 16 kDa protein. Leptin is produced by mature adipocytes and is secreted in plasma. Leptin has been reported to increase lean body mass (Friedman et al., UK Patent Application No. GB 2292382 and Pelleymounter et al., International Patent Application Publication Number WO97/18833) and decrease fat body mass (Halaas et al., Science 269:543-546, 1995). Further, a leptin receptor, OB-R, has been identified and cloned (Tartaglia et al., Cell 83:1263-1271, 1995). Further, leptin has been disclosed to stimulate cortical bone formation in ob/ob mice (Liu et al., Americal Society for Bone and Mineral Research, 19th Annual Meeting, Sep. 10-14, 1997, Cincinati, Ohio).
Skeletal disorders are highly prevalent diseases caused by nutrition deficiency, sex steroid deficiency, aging, trauma or other factors. All approved therapies and clinically advanced candidates including calcitonin, estrogen replacement therapy, bisphosphonates and tissue selective estrogen agonists act to prevent bone loss by inhibiting bone resorption, but these agents cannot restore bone mass. Thus, there is significant medical need for agents that would increase bone mass and strength above a critical threshold in established osteoporotic patients, fractured patients, and other skeletal disorder patients.
This invention is directed to methods for augmenting bone mass and preventing bone loss in a vertebrate, e.g., a mammal (including humans) comprising administering to said vertebrate, e.g., a mammal, a therapeutically effective amount of leptin or a leptin mimetic.
This invention is also directed to methods for treating a vertebrate, e.g. a mammal (including a human being) having a condition which presents with low bone mass comprising administering to said vertebrate, e.g., mammal, having a condition which presents with low bone mass a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, prosthetic ingrowth, or inducing vertebral synostosis in a vertebrate, e.g. a mammal (including a human being) by administering to said vertebrate, e.g., mammal, suffering from or susceptible to osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, prosthetic ingrowth or vertebral synostosis a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating osteoporosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, e.g., mammal, suffering from or susceptible to osteoporosis a therapeutically effective amount of a leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating osteotomy bone loss in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, e.g., a mammal, suffering from or susceptible to an osteotomy bone loss a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating alveolar bone loss in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, e.g., mammal, suffering from or susceptible to an alveolar bone loss a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating bone loss associated with periodontitis in a vertebrate, e.g., a mammal (including a human being) by administering to said vertebrate, suffering from or susceptible to bone loss associated with periodontitis a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating childhood idiopathic bone loss in a child by administering to a child suffering from or susceptible to childhood idiopathic bone loss a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating xe2x80x9csecondary osteoporosisxe2x80x9d, which includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, suffering from or susceptible to xe2x80x9csecondary osteoporosisxe2x80x9d a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating glucocorticoid-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, suffering from or susceptible to glucocorticoid-induced osteoporosis a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating hyperthyroidism-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, .e.g, mammal, suffering from or susceptible to hyperthyroidism-induced osteoporosis a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating immobilization-induced osteoporosis in a vertebrate, e.g., a mammal, (including a human being), by administering to said vertebrate, suffering from or susceptible to immobilization-induced osteoporosis a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating heparin-induced osteoporosis in a vertebrate, e.g., mammal, (including a human being), by administering to said vertebrate, e.g., a mammal suffering from or susceptible to heparin-induced osteoporosis a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, e.g., mammal, suffering from or susceptible to immunosuppressive-induced osteoporosis a therapeutically effective amount of a leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for enhancing bone fracture healing in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, suffering from or susceptible to a bone fracture a therapeutically effective amount of a leptin or leptin mimetic. In one aspect of this invention, leptin or a leptin mimetic is applied locally to the site of bone fracture.
Yet another aspect of this invention is directed to methods for enhancing bone healing following facial reconstruction or maxillary reconstruction or mandibular reconstruction in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, which has undergone facial reconstruction or maxillary reconstruction or mandibular reconstruction a therapeutically effective amount of leptin or a leptin mimetic. In one aspect of this invention, leptin or a leptin mimetic is applied locally to the site of bone reconstruction.
Yet another aspect of this invention is directed to methods for enhancing prosthetic ingrowth in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, in need of enhancing prosthetic ingrowth a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for inducing vertebral synostosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, undergoing surgery for vertebral synostosis a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for enhancing long bone extension in a vertebrate, e.g.,, a mammal (including a human being), by administering to said vertebrate, suffering from or susceptible to an insufficiently sized long bone a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating a bone graft in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, e.g., a mammal, suffering from or susceptible to a bone graft a therapeutically effective amount of leptin or a leptin mimetic. In one aspect of this invention, leptin or a leptin mimetic is applied locally to the site of the bone graft.
Yet another aspect of this invention is directed to methods for treating low bone mass or bone fracture in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, a therapeutically effective amount of leptin or a leptin mimetic, and estrogen.
Yet another aspect of this invention is directed to methods for treating low bone mass or bone fracture in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, a therapeutically effective amount of a leptin or a leptin mimetic, and a selective estrogen receptor modulator.
Preferred selective estrogen receptor modulators include droloxifene, raloxifene, tamoxifen; 4-hydroxy-tamoxifen; toremifene; centchroman; levormeloxifene; idoxifene; 6-(4-hydroxy-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-benzyl)-naphthalen-2-ol; (4-(2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl)-(6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl)-methanone;
3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid;
2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol;
cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
(xe2x88x92)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol;
cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol;
cis-1-(6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
1-(4xe2x80x2-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; and the pharmaceutically acceptable salts thereof.
Especially preferred selective estrogen receptor modulators include raloxifene; droloxifene; idoxifene;
3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid;
2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol;
cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
(xe2x88x92)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol;
cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol;
cis-1-(6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
1-(4xe2x80x2-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; and the pharmaceutically acceptable salts thereof.
Still more especially preferred selective estrogen receptor modulators include raloxifene, droloxifene, idoxifene and (xe2x88x92)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol.
Yet another aspect of this invention is directed to methods for treating low bone mass or bone fracture in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, a therapeutically effective amount of leptin or a leptin mimetic, and a bisphosphonate.
Preferred bisphosphonates include tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid and their pharmaceutically acceptable salts. Those skilled in the art will know that these compounds are often referred to as their ion form, e.g., tiludronate, alendronate, zoledronate, ibandronate, risedronate, etidronate, clodronate and pamidronate.
Especially preferred bisphosphonates include alendronate and risedroate.
Yet another aspect of this invention is directed to methods for enhancing bone healing following facial reconstruction, maxillary reconstruction, mandibular reconstruction, enhancing long bone extension, enhancing the healing rate of a bone graft, enhancing prosthetic ingrowth or inducing vertebral synostosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, a therapeutically effective amount of leptin or a leptin mimetic, and estrogen.
Yet another aspect of this invention is directed to methods for enhancing bone healing following facial reconstruction, maxillary reconstruction, mandibular reconstruction, enhancing long bone extension, enhancing the healing rate of a bone graft, enhancing prosthetic ingrowth or inducing vertebral synostosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, a therapeutically effective amount of leptin or a leptin mimetic, and a selective estrogen receptor modulator.
Yet another aspect of this invention is directed to methods for enhancing bone healing following facial reconstruction, maxillary reconstruction, mandibular reconstruction, enhancing long bone extension, enhancing the healing rate of a bone graft, enhancing prosthetic ingrowth or inducing vertebral synostosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, a therapeutically effective amount of leptin or a leptin mimetic, and a bisphosphonate.
Yet another aspect of this invention is directed to a pharmaceutical composition comprising a leptin mimetic and a pharmaceutically acceptable carrier or diluent.
Yet another aspect of this invention is directed to a pharmaceutical composition comprising leptin or a leptin mimetic, estrogen and a pharmaceutically acceptable carrier or diluent.
Yet another aspect of this invention is directed to a pharmaceutical composition comprising leptin or a leptin mimetic, a selective estrogen receptor modulator; and a pharmaceutically acceptable carrier or diluent.
Yet another aspect of this invention is directed to a pharmaceutical composition comprising leptin or a leptin mimetic, a bisphosphonate; and a pharmaceutically acceptable carrier or diluent.
Yet another aspect of this invention is directed to a kit comprising:
a. leptin or a leptin mimetic in a first unit dosage form;
b. estrogen in a second unit dosage form; and
c. a container.
Yet another aspect of this invention is directed to a kit comprising:
a. leptin or a leptin mimetic in a first unit dosage form;
b. a selective estrogen receptor modulator in a second unit dosage form; and
c. a container.
Yet another aspect of this invention is directed to a kit comprising:
a. leptin or a leptin mimetic in a first unit dosage form;
b. a bisphosphonate in a second unit dosage form; and
c. a container.
Preferably post-menopausal women and men over the age of 60 are treated.
Leptin and fragments thereof are particularly preferred agents in the pharmaceutical compositions and methods of this invention. Leptin is most particularly preferred.
A preferred dosage is about 0.0001 to 1000 mg/kg/day of leptin or a leptin mimetic. An especially preferred dosage is about 0.001 to 100 mg/kg/day of leptin or a leptin mimetic.
The phrase xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d refers to a condition where the level of bone mass is below the age specific normal as defined in standards by the World Health Organization xe2x80x9cAssessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a World Health Organization Study Group. World Health Organization Technical Series 843xe2x80x9d. Included in xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d are primary and secondary osteoporosis. Secondary osteoporosis includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis and immunosuppressive-induced osteoporosis. Also included is periodontal disease, alveolar bone loss, osteotomy bone loss and childhood idiopathic bone loss. The xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d also includes long term complications of osteoporosis such as curvature of the spine, loss of height and prosthetic surgery.
The phrase xe2x80x9ccondition which presents with low bone massxe2x80x9d also refers to a mammal known to have a significantly higher than average chance of developing such diseases as are described above including osteoporosis (e.g., post-menopausal women, men over the age of 60.
Those skilled in the art will recognize that the term bone mass actually refers to bone mass per unit area which is sometimes (although not strictly correctly) referred to as bone mineral density.
The term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein includes preventative (e.g., prophylactic), palliative and curative treatment.
The term xe2x80x9cleptin mimeticxe2x80x9d as used herein means any ligands including recombinant products and small molecules which can bind to and/or activate the leptin receptor (OB-R) and act as receptor agonists. Methods for the recombinant production of leptin have been described by Friedman et al., UK Patent Application No. 2292382.
A fragment of leptin or a leptin fragment is any active portion of the leptin molecule.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
The expression xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene-sulfonate. The expression also refers to nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,Nxe2x80x2-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methylglucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
The term xe2x80x9cmammalxe2x80x9d is meant to include both companion animals and humans. The phrase xe2x80x9ccompanion animalxe2x80x9d refers to a household pet or other domesticated animal such as, but not limited to, cattle, sheep, ferrets, swine, horses, poultry, fish, rabbits, goats, dogs, cats and the like. Particularly preferred companion animals are dogs and cats.
The methods of this invention result in bone formation resulting in decreased fracture rates. This invention makes a significant contribution to the art by providing compounds and methods that increase bone formation resulting in prevention, retardation, and/or regression of osteoporosis and related bone disorders.
Other features and advantages of this invention will be apparent from the specification and appendant claims which describe the invention.